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Some successful Alzheimer’s disease treatments may hinge on predicting who will get disease before they present with symptoms. To that end, many research groups are exploring biomarkers, cognitive tests, and brain imaging as possible ways to spot at-risk individuals before they show neuronal damage or mental deficits. Two functional imaging studies presented at this year’s Society for Neuroscience meeting, held 12-16 November in Washington, DC, suggest that underlying brain function during working memory tasks could herald cognitive decline even while performance on cognitive tests still looks completely normal.

Julie Dumas and colleagues at the University of Vermont in Burlington reported at a November 14 SfN press conference that post-menopausal women with cognitive complaints activate larger portions of their working memory centers when performing a working memory task than those who do not complain of cognitive difficulties. Through a series of questionnaires, the research team categorized 23 post-menopausal women with an average age of 57 years as “complainers” or “non-complainers.” Functional magnetic resonance imaging (fMRI) revealed that, although the 12 complainers performed as well as their content counterparts on a visual/verbal test of working memory, more of the complainers’ dorsolateral prefrontal cortices and anterior cingulate cortices were active.

“We believe that this is a compensation response,” said Dumas. “These cognitive complainers are activating brain regions involved in working memory to a greater extent than non-complainers.” Previous work from Reisa Sperling’s lab at Brigham and Women’s Hospital, Boston, suggested a hyperactivation of the hippocampus, which may also reflect a compensatory mechanism (see Celone et al., 2006).

A previous longitudinal study on a mixed-gender sample of 213 people with an average age of 67 reported that 54 percent of people complaining of cognitive difficulties progressed to mild cognitive impairment (MCI) or dementia within seven years, even though they performed normally on initial cognitive testing. Only 15 percent of those without complaints showed such decline (see Reisberg et al., 2010). The results hint that subjective cognitive impairment is a risk factor for dementia—people may not just be imagining cognitive difficulties. While other factors can account for cognitive problems, Dumas said she controlled for depression, sleep deprivation, and hot flashes in her study and still found differences between groups.

“We’re now showing that these cognitive complaints are important around the age of menopause. We suggest they may be related to future cognitive changes,” said Dumas. She plans to follow these women, half of whom will be treated for three months with estrogen and half with placebo, to see if estrogen mitigates the functional differences between the two groups.

In a related poster presentation by Lucas Broster, a graduate student in the lab of Yang Jiang at the University of Kentucky College of Medicine in Lexington, described a pilot study that used functional data to differentiate between people with MCI and healthy controls in a mixed-gender, older cohort. Broster reported that while people with MCI performed just like healthy controls on a working memory task, electroencephalography (EEG) measurements distinguished the two groups (see Part 1 of a two-part series on EEG).

The research team tested 46 people (average age, 76)—either normal controls or diagnosed with MCI or AD—on a delayed match-to-sample test. Participants memorized an image and then determined whether the following images matched. Cognitively healthy people took the same amount of effort to accept or reject an image. However, individuals with MCI had to work harder to reject an image than they did to accept it, as shown by EEG-measured event related potentials in the left frontal brain. Preliminary data suggest that those with AD also had to work harder to reject an image, though Broster cautioned that these data are not significant in the small number of AD patients studied so far. The team will collect more results to see if the trend holds up. “Differentiating healthy patients versus those with MCI is clinically challenging,” said Broster. “If we find that the task is as sensitive as our pilot data imply, it could have some translational potential for screening people for MCI.”—Gwyneth Dickey Zakaib.